First total synthesis of (+)-11-hydroxyerythratidine

Article abstract of DOI:10.1055/s-0028-1088157

The first total synthesis of (+)-11-hydroxyerythratidine is described. The strategy is featured by a highly stereoselective construction of the C(5) spiro center via the Lewis acid promoted cyclization of ortho-quinone acetal, derived from di-ortho-substituted biphenyl 9 with a chiral center at the side chain. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088157

LETTER
1041
First Total Synthesis of (+)-11-Hydroxyerythratidine
Total
Synthesis
o
of (+)-11-Hy
s
droxyery
h
thratidine io Onoda, Yosuke Takikawa, Takashi Fujimoto, Yoshizumi Yasui, Keisuke Suzuki, Takashi Matsumoto*
Department of Chemistry, Tokyo Institute of Technology and SORST-JST Agency, 2-12-1, O-okayama, Meguro-ku,
Tokyo 152-8551, Japan
Fax +81(3)57343531; E-mail: tmatsumo@chem.titech.ac.jp
Received 31 December 2008
the axial chirality of ortho-‘tri’-substituted biphenyl I is
nicely transmitted into the chirality of spirocycle III via
the Lewis acid promoted cyclization of ortho-quinone
acetal II.
Abstract: The first total synthesis of (+)-11-hydroxyerythratidine
is described. The strategy is featured by a highly stereoselective
construction of the C(5) spiro center via the Lewis acid promoted
cyclization of ortho-quinone acetal, derived from di-ortho-substi-
tuted biphenyl 9 with a chiral center at the side chain.
In further study, we focused on a class of minor erythrinan
alkaloids with additional oxy function at C(11), such as 3
and 4. By an adrenaline-like substructure at the N(9)–
C(17) framework, intriguing biological profiles may be
expectable. However, the synthesis of such C(11)-oxy
compounds has been virtually unexplored; only one race-
mic synthesis has been recorded to date.6,7
Key words: asymmetric synthesis, biphenyls, erythrinan alkaloids,
natural product, spirocenter chirality
Erythrinan alkaloids constitute a class of natural products,
sharing indolo[7a,1-a]isoquinoline skeleton (Figure 1).1,2
These compounds have been popular synthetic targets by
the challenges posed by the unique tetracyclic amino
structures, and also by the physiological significance, ex-
hibiting curare-like, sedative, hypotensive, and central
nerve system depressant activities.1,3,4 Indeed, many syn-
thetic approaches have been developed, though the enan-
tioselective ones are still limited.4
previous work
OMe
OMe
axial
chirality
MeO
MeO
PhI(OAc)2
MeOH
NHBoc
OTIPS
NHBoc
*
*
Me3Si
MeO
Me3Si
MeO
OTIPS
17
11
MeO
MeO
MeO
MeO
MeO
OH
I
9
O
D
C
N
N
N
II
>98% ee
15
13
B
5
6
A
spiro center
chirality
3
1
MeO
MeO
MeO
O
O
N-Boc
BF3⋅OEt2
*
MeO
OTIPS
1
erythratidinone (2)
erythrinan skeleton
OMe
O-methylerysodienone (1)
Me3Si
MeO
stereospecific
cyclization
OH
O
MeO
MeO
MeO
MeO
MeO
III
>98% ee
N
N
Scheme 1 Stereospecific spirocyclization strategy
MeO
OH
We became interested, however, in the possibility that the
chiral center at the side chain in biphenyl IV may direct
the mode of cyclization of ortho-quinone acetal V, allow-
ing the stereocontrolled formation of the C(5) spiro center
(Scheme 2). The key to such a plan was the behavior of
two ortho-quinone acetal rotamers Va and Vb; given they
are rapidly interconverting because of a ortho-‘di’-substi-
tuted biphenyl-like structure, an optimistic assumption
was either the cyclization rate or the equilibrium prefer-
ence of Va and Vb was somehow different enough, en-
abling the diastereoselective cyclization to occur.
11-hydroxyerythratidine (3)
erythristemine (4)
Figure 1 Natural erythrinan alkaloids
We recently reported an enantioselective approach to
these alkaloids via the chiral transmission, and its viability
was demonstrated by the total synthesis of (+)-O-methyl-
erysodienone (1, Scheme 1).5 By installing a TMS group
for retarding the atropisomerization (enantiomerization),
SYNLETT 2009, No. 7, pp 1041–1046
Advanced online publication: 26.03.2009
DOI: 10.1055/s-0028-1088157; Art ID: U13308ST
© Georg Thieme Verlag Stuttgart · New York
2
3.
4
.2
0
0
9
In this communication, we describe the realization of this
scenario, albeit not straightforward, and application to the
first total synthesis of (+)-11-hydroxyerythratidine (3).8

1042
T. Onoda et al.
LETTER
which was coupled with boronic ester 611 by Suzuki–
Miyaura reaction12 (Scheme 3). The reaction with 10
mol% of PdCl2(dppf)·CH2Cl2 (K2CO3, DME–H2O, 60 °C)
cleanly afforded biphenyl aldehyde 7 in 98% yield. The
Wittig methylenation of the formyl group (Ph3P=CH2,
THF), and hydroboration of the resulting olefin
[(Me2CHCHMe)2BH, THF, 0 °C] followed by oxidative
workup (H2O2, aq NaOH) afforded alcohol 8. After pro-
tection of the primary alcohol by a benzoyl (BzCl,
DMAP, pyridine, CH2Cl2), one of the Boc groups on the
nitrogen was removed by treatment with CeCl3·7H2O and
NaI in MeCN (23–25 °C).13 Final removal of the benzyl
group (H2, 10% Pd/C, MeOH) and selective oxidation of
one of the aromatic rings by PhI(OAc)2 (MeOH, 0 °C)
gave the desired ortho-quinone acetal 10 in high yield.14
OMe
this work
MeO
OR1
NHBoc
OR2
*
MeO
IV
OH
OMe
OMe
MeO
MeO
OR1
OR1
NHBoc
NHBoc
*
*
R2O
OR2
MeO
MeO
OMe
OMe
Va
Vb
O
O
At the stage that ortho-quinone acetal 10 was obtained,
NMR analyses (CDCl3 and C6D5CD3) showed us a pessi-
mistic data;15 two rotamers are present in roughly 1:1 ra-
tio, which are interconverting only slowly. Variable-
temperature NMR showed that the rotamer peaks did not
coalesce even at 70 °C (C6D5CD3), and further warming
led to decomposition. The estimated rotational barrier was
>18 kcal/mol, albeit not that high to allow rotamer separa-
tion. Nevertheless, we proceeded to examine the spiro-
cyclization with a hope that the relevant bond rotation
would become dynamic at the key cyclization stage, be-
cause the oxophenonium species 11 would help by the en-
forced planarity from contribution of the extended
quinone-type resonances as 12a and 12b (Scheme 4).
diastereoselective
cyclization
OR1
*
OR1
MeO
MeO
MeO
*
*
N-Boc
N-Boc
OR2
MeO
OR2
*
MeO
MeO
O
O
VIa
VIb
Scheme 2 Diastereoselective spirocyclization strategy
As the enantiomerically pure spirocyclization precursor,
ortho-quinone acetal 10 was prepared starting from aryl
iodide 5 {[a]D –11 (c 0.92, CHCl3), >99.5% ee},9,10
26
OTIPS
MeO
MeO
N(Boc)2
OMe
OMe
MeO
MeO
MeO
5
I
OTIPS
N(Boc)2
OTIPS
N(Boc)2
i) PdCl2(dppf)·CH2Cl2
K2CO3
ii) Ph3P=CH2
CHO
OH
DME–H2O
98%
iii) (sia)2BH
then H2O2, OH–
O
O
B
MeO
79%
CHO
OBn
OBn
7
8
MeO
6
OBn
OMe
OMe
MeO
MeO
MeO
MeO
OTIPS
NHBoc
OTIPS
NHBoc
iv) BzCl
vi) Pd/C, H2
v) CeCl3⋅7H2O
NaI
vii) PhI(OAc)2
MeOH
OBz
OBz
82%
99%
MeO
OBn
O
9
10
Scheme 3 Reagents and conditions: i) 60 °C, 6 h; ii) THF, r.t., 1 h (80%); iii) THF, 0 °C, 2 h (99%); iv) DMAP, pyridine, CH2Cl2, r.t., 40
min (99%); v) MeCN, 23–25 °C, 37 h (83%); vi) MeOH, r.t., 2 h (quant.); vii) 0 °C, 1.5 h (99%).
Synlett 2009, No. 7, 1041–1046 © Thieme Stuttgart · New York

LETTER
Total Synthesis of (+)-11-Hydroxyerythratidine
1043
Table 1 Spirocyclization of ortho-Quinone Acetal 10
OMe
OMe
MeO
MeO
OTIPS
NHBoc
MeO
OTIPS
Lewis acid
– MeOH
Lewis acid
NHBoc
10
OBz
solvent
MS 4A
–20 to 25 °C
+
OBz
MeO
MeO
O
10
O
11
OTIPS
OTIPS
MeO
MeO
MeO
MeO
MeO
OMe
OMe
NBoc
NBoc
OBz
OBz
MeO
MeO
MeO
OTIPS
OTIPS
NHBoc
NHBoc
MeO
13a
13b
O
O
BzO
OBz
Entry Lewis acid
(equiv) Solvent
Yield (%) 13a/13b
OMe
1
2
3
4
5
6
7
8
BF3·OEt2
TMSOTf
Yb(OTf)3
Cu(OTf)2
BF3·OEt2
TMSOTf
Yb(OTf)3
Cu(OTf)2
0.5
0.3
0.3
0.3
0.5
0.3
0.3
0.4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
76
55
75
55
65
55
35
95
1:1
O
O
12a
12b
1:1.2
1.3:1
2.4:1
1:1.5
1:1.2
14:1
14:1
Scheme 4
Based on our previous experiences in related cycliza-
tions,5 we first examined BF3·OEt2, TMSOTf and some
other metal triflates (CH2Cl2, MS4A, –20 °C to 25 °C).
Selected results are shown in Table 1. The reaction pro-
ceeded reasonably well with BF3·OEt2, TMSOTf,
Yb(OTf)3, or Cu(OTf)2, though the stereoselectivity was
not spectacular so long as CH2Cl2 was used as the solvent
(entries 1–4). However, we found a remarkable solvent ef-
fect; Cu(OTf)2 in toluene specifically led to the excellent
result — the desired spirocycle 13 was obtained in 96%
yield in favor of 13a in a 14:1 ratio (entry 8).16
The predominance of 13a could be explained as follows
(Scheme 6): If one assume the pseudo-equatorial place-
ment of the bulky (triisopropylsilyl)oxy group in the tran-
sition state with half-chair-like conformation, two
possible transition structures are TS-a (leading to 13a)
and TS-b (leading to 13b). Among these, TS-b is less fa-
vored by steric repulsion as shown, letting aside the spe-
cific role of Cu(OTf)2 and the solvent effect.
The stereostructure of the major isomer 13a was deter-
mined by X-ray crystallography after derivatization to
diol 14 [(1) n-Bu4NF, THF, –78 °C to 0 °C; (2) K2CO3,
MeOH, –20 °C to r.t.],17 thereby showing the S-configura-
tion of the spiro stereogenic center, needed for the erythri-
nan alkaloids (Scheme 5).1
Having secured the key spiro center, our focus was shifted
to the synthesis of 11-hydroxyerythratidine (3),8 one of
the C(11)-oxygenated erythrinan alkaloids.
Scheme 5 Conversion of spirocycle 13a into diol 14 and the X-ray crystal structure of 14. Reagents and conditions: i) THF, –78 °C to 0 °C,
3 h (quant.); ii) –20 °C to r.t., 6 h (93%).
Synlett 2009, No. 7, 1041–1046 © Thieme Stuttgart · New York

1044
T. Onoda et al.
LETTER
OMe
OMe
OH
O
MeO
MeO
MeO
MeO
MeO
MeO
i) TsCl, DMAP
ii) IBX
OR
OR
NHBoc
NHBoc
N-Boc
N
OH
RO
iii) Me3SiOTf
then
MeOH, buffer
+
+
OR
MeO
MeO
MeO
O
14
O
OMe
66%
O
11a
O
15
11b
O
RO
MeO
MeO
iv) H2
Pd/Al2O3
vi) Li(s-Bu)3BH
74%
7
N
H
+
H
N
H
N
OMe
O
H
H
v) tBuMe2SiCl
imidazole
H
H
Boc
H
Boc
H
3
+
RO
RO
MeO
O
2
10
10
7
H
OR
58%
OMe
16: R = H
17: R = TBDMS
RO
TS-a
TS-b
OH
11
OAc
MeO
MeO
MeO
MeO
MeO
vii) Ac2O
viii) nBu4NF
11
13a
13b
N
N
ix) IBX
81%
Scheme 6 Proposed transition-state structures for the spirocycliza-
tion [the bold lines in TS-a and TS-b represent the side view of the
aromatic ring (the ring D)]
3
MeO
OTBDMS
O
18
19
For the B-ring cyclization, the primary alcohol in diol 14
{[a]D –1.5 (c 1.2, CHCl3), >99.5% ee} was selectively
OH
11
28
MeO
x) K2CO3
MeOH
tosylated (TsCl, pyridine, CH2Cl2, 0 °C) and the remain-
ing alcohol was oxidized [o-iodoxybenzoic acid (IBX),
DMSO].18,19 Upon removal of the Boc group via forma-
tion of the trimethylsilyl carbamate (TMSOTf, CH2Cl2, 0
°C)20 and subsequent hydrolysis (MeOH, pH 7 phosphate
buffer), the desired B-ring cyclization spontaneously pro-
ceeded to give tetracycle 15 (Scheme 7), with a complete
erythrinan skeleton as well as the functionalities ready for
further transformations.
xi) Li(s-Bu)3BH
81%
N
MeO
91%
MeO
O
20
OH
MeO
MeO
11
N
Selective hydrogenation of the C(3)–C(4) double bond
necessitated considerable trials, but was finally effected
by using 5% Pd on alumina as the catalyst [H2 (1 atm),
H2O–EtOH (1:5)]. Simultaneously the C(2) carbonyl un-
derwent reduction, presumably via hydrogenation of the
enol tautomer from the less hindered a-face to give 2,3-
cis-alcohol 16 exclusively.21,22 Alcohol 16, thus obtained,
was protected by a tert-butyldimethylsilyl (TBDMS)
group (TBDMSCl, imidazole, DMF, 0 °C).
MeO
OH
11-hydroxyerythratidine (3)
Scheme 7 Synthesis of (+)-11-hydroxyerythratidine (3). Reagents
and conditions: i) pyridine, 0 °C, 1.5 h (74%); ii) DMSO, r.t., 2.5 h
(93%); iii) CH2Cl2, 0 °C, 3 h (96%); iv) H2O–EtOH (1:5), r.t., 4.5 h;
v) DMF, 0 °C, 1 h (58%, 2 steps); vi) THF, –78 °C to 0 °C, 2 h (74%);
vii) DMAP, pyridine, 0 °C, 1 h (93%); viii) THF, r.t., 2 d (92%); ix)
DMSO, r.t., 1 h (95%); x) r.t., 1.5 h (91%); xi) THF, –78 °C to 0 °C,
1 h (81%).
Reduction of the C(11) carbonyl in 17 with Li(s-Bu)3BH
(THF, –78 °C to 0 °C) gave the corresponding 11b-alco-
hol 18 exclusively,23,24 which was then converted into
ketone 19 in three steps including acetylation of the C(11)
hydroxy (Ac2O, DMAP, pyridine, 0 °C), removal of the
TBDMS group (n-Bu4NF, THF), and oxidation of the re-
sulting C(2) hydroxy group by IBX (DMSO).
Upon treatment with K2CO3 in MeOH, ketone 19 cleanly
underwent epimerization at C(3) and deacetylation to give
alcohol 20 in 91% yield, whose stereostructure was unam-
biguously determined by X-ray crystal structure analysis
(Figure 2).17,22
Figure 2 The X-ray crystal structure of 20 and the observed NOE
Synlett 2009, No. 7, 1041–1046 © Thieme Stuttgart · New York

LETTER
Total Synthesis of (+)-11-Hydroxyerythratidine
1045
(5) (a) Yasui, Y.; Koga, K.; Suzuki, K.; Matsumoto, T. Synlett
2004, 615. (b) Yasui, Y.; Suzuki, K.; Matsumoto, T. Synlett
2004, 619.
Finally, reduction of the C(2) carbonyl with Li(s-Bu)3BH
(THF, –78 °C to 0 °C) proceeded exclusively in an a-
selective manner to complete the first synthesis of 11-
(6) Isobe, K.; Mohri, K.; Takeda, N.; Hosoi, S.; Tsuda, Y.
24
hydroxyerythratidine (3) {[a]D +203 (c 1.1, CHCl3),
J. Chem. Soc., Perkin Trans. 1 1989, 1357.
>99.5% ee}.25,26
(7) The semisynthesis involving oxidation of the C(11)
methylene of the natural substance: (a)Isobe, K.; Mohri, K.;
Suzuki, K.; Haruna, M.; Ito, K.; Hosoi, S.; Tsuda, Y.
Heterocycles 1991, 32, 1195. Also see: (b) Isobe, K.;
Mohri, K.; Takeda, N.; Suzuki, K.; Hosoi, S.; Tsuda, Y.
Chem. Pharm. Bull. 1994, 42, 197.
(8) (a) Chawla, A. S.; Jackson, A. H. Nat. Prod. Rep. 1990, 565.
(b) Soto-Hernandez, M.; Jackson, A. H. Planta Med. 1994,
60, 175. (c) Jackson, A. H.; Chawla, A. S. Allertonia 1982,
3, 39.
In summary, we have accomplished the first total synthe-
sis of 11-hydroxyerythratidine (3). The key step was the
Lewis acid promoted cyclization of ortho-quinone acetal
10 to effect the construction of the chiral spiro center at
C(5) in highly diastereoselective manner. This synthesis
demonstrates a new application of biphenyl derivative as
a scaffold for stereocontrolled and convenient assembly
of polycyclic structures in natural product synthesis. Fur-
ther application of this methodology is now under investi-
gation in our laboratory.
(9) Iodide 5 (>99.5% ee) was prepared from varatraldehyde via
the Sharpless asymmetric dihydroxylation (Scheme 8). See
Supporting Information.
OH
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
i) Ph3P=CH2
MeO
MeO
CHO
MeO
MeO
OH
ii) AD-mix-α
Acknowledgment
veratraldehyde
78%
99.0% ee → >99.5% ee
(recrystallization)
This work was supported by Ministry of Education, Culture, Sports,
Science, and Technology, Japan [Grant-in-Aid for Science Re-
search on Priority Areas (No.16073210)] and partially by the Glo-
bal COE program (Tokyo Institute of Technology).
OTIPS
N(Boc)2
MeO
MeO
66%
5
I
>99.5% ee
References and Notes
Scheme 8
(1) (a) Dyke, S. F.; Quessy, S. N. In The Alkaloids, Vol. 18;
Rodrigo, R. G. A., Ed.; Academic Press: New York, 1981,
1. (b) Tsuda, Y.; Sano, T. In The Alkaloids, Vol 48; Cordell,
G. A., Ed.; Academic Press: San Diego, 1996, 249.
(c) Grove, J. F.; Reimann, E.; Roy, S. In Progress in the
Chemistry of Organic Natural Products, Vol. 88; Herz, W.;
Falk, H.; Kirby, G. W., Eds.; Springer: Wien / New York,
2007, 1.
(2) Throughout this work, the commonly accepted erythrinan
numbering is used. See: Boekelheide, V.; Prelog, V. In
Progress in Organic Chemistry, Vol. 3; Cook, J. W., Ed.;
Butterworths Scientific: London, 1955, Chap. 5; see also
ref. 1.
(3) Recent examples of the total syntheses in racemic form:
(a) Padwa, A.; Wang, Q. J. Org. Chem. 2006, 71, 7391.
(b) Gao, S.; Tu, Q. Y.; Hu, X.; Wang, S.; Hua, R.; Jiang, Y.;
Zhao, Y.; Fan, X.; Zhang, S. Org. Lett. 2006, 8, 2373.
(c) Wang, Q.; Padwa, A. Org. Lett. 2006, 8, 601.
(d) Shimizu, K.; Takimoto, M.; Mori, M. Org. Lett. 2003, 5,
2323. (e) Fukumoto, H.; Esumi, T.; Ishihara, J.;
Hatakeyama, S. Tetrahedron Lett. 2003, 44, 8047. (f) Lee,
H.; Cassidy, M. P.; Rashatasakhon, P.; Padwa, A. Org. Lett.
2003, 5, 5067. (g) Hosoi, S.; Nagao, M.; Tsuda, Y.; Isobe,
K.; Sano, T.; Ohta, T. J. Chem. Soc., Perkin Trans. 1 2000,
1505.
(4) The total syntheses in optically active form: (a)Blake, A.J.;
Gill, C.; Greenhalgh, D. A.; Simpkins, N. S.; Zhang, F.
Synthesis 2005, 3287. (b) Allin, S. M.; Streetley, G. B.;
Slater, M.; James, S. L.; Martin, W. P. Tetrahedron Lett.
2004, 45, 5493. (c) Tsuda, Y.; Hosoi, S.; Katagiri, N.;
Kaneko, C.; Sano, T. Chem. Pharm. Bull. 1993, 41, 2087.
(d) Tsuda, Y.; Hosoi, S.; Katagiri, N.; Kaneko, C.; Sano, T.
Heterocycles 1992, 33, 497.
(10) The reaction with the corresponding mono-Boc derivative
was not fruitful.
(11) Boronic ester 6 was synthesized in three steps from
isovanillin (Scheme 9). For the palladium-catalyzed boronic
ester formation with bis(pinacolato)diboron, see:
(a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem.
1995, 60, 7508. (b) Ishiyama, T.; Ishida, K.; Miyaura, N.
Tetrahedron 2001, 57, 9813.
Br
CHO
CHO
i) BnBr, NaOH
MeO
ii) Br2, AcOH,
NaOAc
MeO
OH
OBn
2 steps, 57%
O
O
O
O
B
B
O
O
B
CHO
PdCl2(dppf)⋅CH2Cl2
KOAc
MeO
84%
OBn
6
Scheme 9
(12) (a) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N.
Tetrahedron Lett. 1997, 38, 3447. (b) For a review, see:
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
Synlett 2009, No. 7, 1041–1046 © Thieme Stuttgart · New York

1046
T. Onoda et al.
LETTER
(13) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. S. Synlett 2002,
468.
(14) Recent reviews of quinone acetals, see: (a) Magdziak, D.;
Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104, 1383.
(b) Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008,
467.
(23) Reimann, E.; Ettmayr, C. Monatsh. Chem. 2004, 135, 959.
(24) The 11b-configuration of 18 was confirmed by employing
its C(11) epimer 22 (Scheme 10), obtained as the minor
isomer by the reduction with NaBH4 (MeOH, r.t.), in which
the NOE was observed between the hydrogens at C(8) and
C(11).
(15) (a) Curtin, D. Y. Rec. Chem. Prog. 1954, 15, 111.
(b) Seeman, J. I. Chem. Rev. 1983, 83, 83.
(16) Experimental Procedure
O
OH
MeO
MeO
MeO
MeO
To a suspension of 4 Å MS (3.05 g) and Cu(OTf)2 (1.06 g,
2.09 mmol) in toluene (13 mL) was added dropwise ortho-
quinone acetal 10 (4.36 g, 5.78 mmol) in toluene (25 mL) at
–20 °C, and the mixture was allowed to warm to 25 °C. After
stirring for 13 h, the reaction was quenched by adding sat. aq
NaHCO3. The mixture was filtered through a Celite pad and
the products were extracted with EtOAc (3×). The combined
organic extracts were washed with brine, dried over Na2SO4,
and concentrated in vacuo. The residue was purified by flash
column chromatography (hexane–EtOAc, 3:2) to afford
spirocycle 13a (3.75 g, 90%) and 13b (261 mg, 6%).
(17) Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 712628 (for compound 14) and
712629 (for compound 20). Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1 EZ, UK [fax:+44 (1223)336033 or
e-mail: deposit@ccdc.cam.ac.uk]; http://www.ccdc.cam.ac.uk/
products/csd/deposit/.
NaBH4
N
N
18
+
MeOH
73%
MeO
MeO
22/18 = 1:1.3
OTBDMS
MeO
OTBDMS
17
22
H = 4.98
OMe
δ
(dd, J = 9.5, 6.8 Hz)
OH
11
H
n.O.e
MeO
H
N
TBDMSO
8
H
H
δH = 2.88
H
(ddd, J = 8.9, 8.9, 6.0 Hz)
22
Scheme 10
(25) The preference of the hydride attack from the b-face could
be ascribed to the steric hindrance to the a-attack by the axial
hydrogen at C(4).
(18) (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994,
35, 8019. (b) Frigerio, M.; Santagostino, M.; Sputore, S.
J. Org. Chem. 1999, 64, 4537.
(19) Attempted cyclizations of the derivatives possessing
hydroxy or protected hydroxy at C(11) resulted in affording
tetracyle 21 (Figure 3) with C(10)–C(11) double bond in
various yields.
(26) (+)-11-Hydroxyerythratidine (3)
Mp 188.5–190.3 °C (hexane–CHCl3); [a]D24 +203 (c 1.1,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.82 (dd, 1 H,
J1 = 12.5 Hz, J2 = 11.6 Hz), 1.93 (dd, 1 H, J1 = 11.6 Hz,
J2 = 4.1 Hz), 2.00–2.25 (br, 2 H), 2.20–2.30 (m, 1 H), 2.40–
2.60 (m, 1 H), 3.02 (ddd, 1 H, J1 = J2 = 9.3 Hz, J3 = 6.8 Hz),
3.14 (ddd, 1 H, J1 = J2 = 9.3 Hz, J3 = 3.0 Hz), 3.29 (dd, 1 H,
J1 = 15.4 Hz, J2 = 1.2 Hz), 3.35 (s, 3 H), 3.62 (ddd, 1 H,
J1 = 12.5 Hz, J2 = J3 = 4.1 Hz), 3.73 (dd, 1 H, J1 = 15.4 Hz,
J2 = 5.7 Hz), 3.83 (s, 3 H), 3.91 (s, 3 H), 4.44–4.54 (br, 1 H),
4.56–4.66 (br, 1 H), 5.86–5.94 (br, 1 H), 6.50 (s, 1 H), 7.06
(s, 1 H). 13C NMR (100 MHz, CDCl3): d = 27.5, 35.5, 48.8,
50.5, 55.9, 56.1, 56.5, 62.9, 63.3, 64.7, 76.2, 109.8, 111.8,
120.8, 128.2, 128.3, 145.6, 148.0, 148.7. IR (ATR): 3393,
2926, 2866, 2852, 1509, 1462, 1255, 1101, 1057, 981, 873,
778, 750 cm–1. Anal. Calcd for C19H25NO5: C, 65.69; H,
7.25; N, 4.03. Found: C, 65.48; H, 7.55; N, 3.83. HPLC
[CHIRALCEL® OD-H (Daicel), Ø 0.46 × 25 cm (2×),
hexane–2-PrOH (4:1), 1.0 mL/min, 30 °C, 254 nm] tR = 12.6
min for 3 (15.4 min for ent-3). NOE was observed between
the hydrogens at C(2) and C(14) (Figure 4).
MeO
N
MeO
MeO
O
21
Figure 3
(20) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870; and
references cited therein.
(21) a-Orientation of the C(2)hydrogen in 16–18 was deduced as
follows:(1) The assumed ketone intermediate, though not
detected, was supposed to be prone to enolization at the C(2)
carbonyl to be hydrogenated [cf. epimerization of ketone 19
at C(3)];(2) in compounds 16–18, the NOE was not observed
between the hydrogens at C(2) and C(14) while observed in
compound 3 with 2b-hydrogen (see ref. 26).
(22) Acetylation of 20 [Ac2O, DMAP, pyridine] gave the
stereoisomer of ketone 19, which obviously shows that the
conversion of 19 into 20 was the two-step process including
the deacetylation and the epimerization at C(3). Because
a-orientation of the C(3) methoxy in 20 was confirmed by
X-ray crystal structure analysis, it leads to b-orientation of
the C(3) methoxy in compound 19 as well as 16–18.
OMe
δH = 6.50 (s)
MeO
H14
H
n.O.e
OH
H
δH = 4.44–4.54
H
(br)
MeO
HO
N
2
11-hydroxyerythratidine (3)
Figure 4
Synlett 2009, No. 7, 1041–1046 © Thieme Stuttgart · New York

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